Danny Petrasek

Requirements for Calibration in Noninvasive Glucose Monitoring by Raman Spectroscopy

Background: In the development of noninvasive glucose monitoring technology, it is highly desirable to derive a calibration that relies on neither person-dependent calibration information nor supplementary calibration points furnished by an existing invasive measurement technique (universal calibration). Method: By appropriate experimental design and associated analytical methods, we establish the sufficiency of multiple factors required to permit such a calibration. Factors considered are the discrimination of the measurement technique, stabilization of the experimental apparatus, physics-physiology-based measurement techniques for normalization, the sufficiency of the size of the data set, and appropriate exit criteria to establish the predictive value of the algorithm. Results: For noninvasive glucose measurements, using Raman spectroscopy, the sufficiency of the scale of data was demonstrated by adding new data into an existing calibration algorithm and requiring that (a) the prediction error should be preserved or improved without significant re-optimization, (b) the complexity of the model for optimum estimation not rise with the addition of subjects, and (c) the estimation for persons whose data were removed entirely from the training set should be no worse than the estimates on the remainder of the population. Using these criteria, we established guidelines empirically for the number of subjects (30) and skin sites (387) for a preliminary universal calibration. We obtained a median absolute relative difference for our entire data set of 30 mg/dl, with 92% of the data in the Clarke A and B ranges. Conclusions: Because Raman spectroscopy has high discrimination for glucose, a data set of practical dimensions appears to be sufficient for universal calibration. Improvements based on reducing the variance of blood perfusion are expected to reduce the prediction errors substantially, and the inclusion of supplementary calibration points for the wearable device under development will be permissible and beneficial.

Intrinsic frequency for a systems approach to haemodynamic waveform analysis with clinical applications

The reductionist approach has dominated the fields of biology and medicine for nearly a century. Here, we present a systems science approach to the analysis of physiological waveforms in the context of a specific case, cardiovascular physiology. Our goal in this study is to introduce a methodology that allows for novel insight into cardiovascular physiology and to show proof of concept for a new index for the evaluation of the cardiovascular system through pressure wave analysis. This methodology uses a modified version of sparse time–frequency representation (STFR) to extract two dominant frequencies we refer to as intrinsic frequencies (IFs; ω1 and ω2). The IFs are the dominant frequencies of the instantaneous frequency of the coupled heart + aorta system before the closure of the aortic valve and the decoupled aorta after valve closure. In this study, we extract the IFs from a series of aortic pressure waves obtained from both clinical data and a computational model. Our results demonstrate that at the heart rate at which the left ventricular pulsatile workload is minimized the two IFs are equal (ω1 = ω2). Extracted IFs from clinical data indicate that at young ages the total frequency variation (Δω = ω1 − ω2) is close to zero and that Δω increases with age or disease (e.g. heart failure and hypertension). While the focus of this paper is the cardiovascular system, this approach can easily be extended to other physiological systems or any biological signal.

Systems Biology: The Case for a Systems Science Approach to Diabetes

The unprecedented accumulation of biological data in recent decades has underscored the need to organize and integrate the massive collection of information. In addition, there is rising agreement among biologists that a complete understanding of a single cell will not lead directly to a complete understanding of a system of cells. The success of a systems science approach in engineering and physics may be of great value in the evolution of biological science. This article reviews some examples that suggest the importance of a systems biology approach and, in addition, advance one specific systems science principle, the conservation of uncertainty, which may give insight into the emergent behavior of numerous biological and physiological phenomena.

A computational model of 1,5‐AG dynamics during pregnancy

The importance of 1,5‐anhydroglucitol (1,5‐AG) as an intermediate biomarker for diabetic pregnancy is multi‐fold: (1) it serves as a reliable indicator of moderate‐level glycemic control, especially during early gestation; (2) it has been associated with increased risk of diabetes, independent of HbA1c and fasting glucose; and (3) it is an independent risk factor for the development of eclampsia during pregnancy. However, the clinical use of this biomarker during pregnancy has been underutilized due to physiological changes in glomerular filtration rate, plasma volume, and other hemodynamic parameters which have been hypothesized to bias gestational serum 1,5‐AG concentrations. Here, we develop an in‐silico model of gestational 1,5‐AG by combining pre‐existing physiological data in the literature with a two‐compartment mathematical model, building off of a previous kinetic model described by Stickle and Turk ( ) Am. J. Physiol., 273, E821. Our model quantitatively characterizes how renal and hemodynamic factors impact measured 1,5‐AG during normal pregnancy and during pregnancy with gestational diabetes and diabetes mellitus. During both normal and diabetic pregnancy, we find that a simple two‐compartment model of 1,5‐AG kinetics, with all parameters but reabsorption fraction adjusted for time in pregnancy, efficiently models 1,5‐AG kinetics throughout the first two trimesters. Allowing reabsorption fraction to decrease after 25 weeks permits parameters closer to expected physiological values during the last trimester. Our quantitative model of 1,5‐AG confirms the involvement of hypothesized renal and hemodynamic mechanisms during pregnancy, clarifying the expected trends in 1,5‐AG to aid clinical interpretation. Further research and data may elucidate biological changes during the third trimester that account for the drop in 1,5‐AG concentrations, and clarify physiological differences between diabetes subtypes during pregnancy.

Intrinsic Frequency and the Single Wave Biopsy: Implications for Insulin Resistance.

Insulin resistance is the hallmark of classical type II diabetes. In addition, insulin resistance plays a central role in metabolic syndrome, which astonishingly affects 1 out of 3 adults in North America. The insulin resistance state can precede the manifestation of diabetes and hypertension by years. Insulin resistance is correlated with a low-grade inflammatory condition, thought to be induced by obesity as well as other conditions. Currently, the methods to measure and monitor insulin resistance, such as the homeostatic model assessment and the euglycemic insulin clamp, can be impractical, expensive, and invasive. Abundant evidence exists that relates increased pulse pressure, pulse wave velocity (PWV), and vascular dysfunction with insulin resistance. We introduce a potential method of assessing insulin resistance that relies on a novel signal-processing algorithm, the intrinsic frequency method (IFM). The method requires a single pulse pressure wave, thus the term “ wave biopsy.”

The virtual hospital: the emergence of telemedicine

The current practice of medicine, while utilizing the advances in biological and physical science, still takes place in the physician office or hospital. Unfortunately, traditional practice as integrated into the current Healthcare system is unsustainable. Accommodating the increase demand for medical services with the attendant rising costs has caused a crisis in healthcare. Telemedicine, the practice of medicine by means of mobile/internet is a transformative process that will impact healthcare globally. Already, teleradiology (diagnostic radiology remotely by means of digital images that are electronically exported) and electronic medical records are gaining wide acceptance. The ability to distribute medical services by means of mobile and internet technology is a natural and almost irresistible direction for the field of Medicine. The healthcare crisis has created an opportunity for new solutions and mobile/Internet technology has laid the infrastructure upon which one can build a powerful, innovative and badly needed platform for health services: The Global Virtual Hospital (GVH). The GVH will be a group of connected centers around the world that overlap (in time zones) throughout the working day. Patients will have access through the Internet or mobile phones. Medical records will be electronically stored, shared among authorized personal and updated with each medical interaction. The GVH, will serve as a platform and laboratory for the creation of innovative devices and technology that will improve the remote interaction.The Global Virtual Hospital System will exemplify the convergence of technology and medicine and will be integrated into standard practice in the next 5-10 year.

Analysis of the Performance of the Software/Hardware Product MyDiaBase+RxChecker for Assessing Treatment Regimens

In 2008, the Action to Control Cardiovascular Risk in Diabetes trial was halted due to an unexpected number of deaths in the intensive treatment group (aiming for hemoglobin A1c levels less than 6%). Hypoglycemic episodes were thought by some to be a contributing cause, underscoring again the challenge of maintaining tight control while avoiding dangerous excursions into hypoglycemic territory. Albisser and colleagues present a set of articles in this issue of Journal of Diabetes Science and Technology that describe a clinical product developed specifically for this timeless clinical conundrum.

Regarding the Announcement to Halt the Intensive Glucose Lowering Arm of the Action to Control Cardiovascular Risk in Diabetes

An announcement to halt the intensive glucose lowering arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial has received tremendous press recently. The basis for stopping the trial was that more deaths from cardiovascular events were noted in the treatment group.1 No specific cause has been identified as yet. Past studies that aimed for “tight” control such as the Diabetes Control and Complications Trial (DCCT)2 have concluded that lower hemoglobin A1c levels were associated with improved cardiovascular health. The new findings appear to contradict this conclusion. One important difference in the ACCORD trial is the study population. In the DCCT trial, exclusion criteria eliminated concurrent hypertension and hyperlipidemia, whereas in the ACCORD study, one of the objectives was to examine the effect of intensive glycemic lowering in subjects who had concurrent hyperlipidemia and hypertension. A known mathematically described principle in control engineering (conservation of uncertainty) states that every connected system has a conserved or constant amount of uncertainty and that attempts to rein in more certainty in one area automatically create uncertainty in another area. When applying this principle to physiology, and in particular the ACCORD study, it is conceivable that attempts to constrain or increase certainty in glycemic control, blood pressure, and hyperlipidemia all at the same time, may be inducing uncertainty or vulnerability in other physiological functions, potentially resulting in a catastrophic event. For a review of this principle, refer to the Journal of Diabetes Science and Technology commentary article.3 In light of recent ACCORD findings, it will be important to consider a range of potential mechanisms and explanations that may be at play. The conservation of the uncertainty principle, in fact, predicts the consequences resulting from restricting the systems range of physiological responses. These consequences might include increased fragility in the microvasculature, leading to myocardial infarction, stroke, or unwanted adverse effects, such as increased risk of hypoglycemia or other neuroendocrine problems. A precise event cannot be specified without a detailed model of the systems complete physiology. Moving forward, when dealing with the complexity of several interconnected physiological functions, careful consideration should be given to studying the system biology along with the specific molecular and cellular mechanisms.